Diaryl and arylthienyl alkyl-amines and process for preparing the same



United States Patent DIARYL AND ARYLTHIENYL ALKYL- AMINES AND PROCESS FOR PRE- PARING THE SAME Karl Kindler, Wentorf, and Werner Hansen, Hamburg- Volkstlorf, Germany, assignors to Chemische Fabrik Promonta G. m. b. H., Hamburg, Germany N Drawing. Application June 1, 1955 Serial No. 512,576

Claims priority, application Germany June 5, 1954 9 Claims. (Cl. 260--247.1)

a process for the preparation of said novel derivatives.

The compounds embodying the present invention correspond to the general formula OH""CflH-(CH2)n-X wherein R stands for an aryl or thienyl radical, R stands for H or alkyl, X stands for the amine radical and n is an integer and meets the condition n 1.

The compounds according to the invention can be used for therapeutic applications, for example for local anesthesia.

In carrying out the present invention a phenylalkyl halogenide, particularly a phenyl alkyl chloride of the formula C H (CH ),,.Cl is used as starting material and a hydrogen atom of the phenyl group is substituted by a benzyl radical or thenyl radical. Subsequently, the Cl atom is substituted according to conventional methods by an amine radical.

Substitution of the H atom can be eiiected according to two procedures. According to a first procedure, the phenylalkyl chloride is reacted in the presence of a suitable catalyst, e. g. an iron compound, such as FeCl or Fe O with a halogenide, preferably a chloride, of the general formula i in order to form a compound of the formula CB-CaHr-(CH2),;.C1

wherein the symbols R, R and n have the meaning defined above. Subsequently the Cl atom of the compound formed is exchanged by an amine radical, in conventionall manner. According to the second procedure, the chloride C H --(CH ),,.Cl is first subjected to chloromethylation. .The dichloride thus obtained, which has the formula Cl.CH -C H (CH ),,.Cl, is reacted in the presence of suitable catalysts, e. g. iron compounds, with a compound of the formula R.H (in which R stands for an aryl or thienyl radical) to form a compound of the formula R.CH -C H (CH ),,.C1. Finally, the C1 atom of the latter is exchanged in conventional manner with an amine radical. 1

Thus, the chlorides are reacted in the presence of suitable iron compounds, e. g. FeCl or Fe O for exice ample with benzyl chloride. Thereby HCl is split oif and a benzyl phenylalltyl chloride is formed, in which the Cl atom is exchanged in conventional manner with a basic radical, for example according to the following scheme:

wherein X is the amine radical and n l.

instead of benzyl chloride, its derivatives can be used, in which the side chain contains alkyl radicals, e. g. a methyl radical, or the benzene radical is substituted e. g. by P, Cl, Br or a methoxy radical. Thenyl chloride and its derivatives, e. g. S-chlorothenyl chloride can also be substituted for benzyl chloride.

The same products can be likewise obtained by the following reactions:

A phenylalkyl chloride, the alkyl of which contains a chain including at least two C-atoms, is subjected to chloromethylation and the resulting dichloride is reacted,

in the presence of suitable iron compounds as catalyst,

with an aromatic compound, such as anisol, o-chloroanisol, o-butoxytoluene, diphenyl ether, naphthalene, 1,2, 3,4-tetrahydronaphthalene or thiophene or its derivatives, e. g. Z-chlorothiophene. Thereby an H atom of these compounds (RH) reacts with the Cl atom of the chloromethyl radical with the formation of HCl:

In the m-onochloride thus obtained, the Cl atom is sub stituted again in conventional manner by an amine radical.

In carrying out the process of this invention it is essential that the catalysts, which may also be compounds of other metals, e. g. compounds of aluminum, be used in minimum amounts.

The following examples show some embodiments of and best modes of carrying out the invention, to which the invention is not limited.

EXAMPLE 1 N-(p-benzylphenylpropyl) -piperidine To 46 parts of 'y-phenylpropyl chloride 0.022 part of anhydrous FeCl or 1e 0,, are added. Into this mixture, 12.7 parts benzyl chloride are slowly introduced, e. g. by adding drop by drop, under heating to about C. and passing dry air through the-mixture. The reaction is completed as soon as the formation of HCl ceases. After cooling, thereaction mass is diluted with some ether or benzene and is washed successively with hydrochloric acid, sodium bicarbonate solution and water. Subsequently, the excess of phenylpropyl chloride is removed by distillation under reduced pressure and the residue is reacted with about an equal amount of piperidine at C. The hydrochloric acid solution of the reaction product is washed with ether or benzene and is then rendered alkaline with KOH, whereby, in addition to the unchanged piperidine, the desired piperidine derivative is likewise separated. After the conventional "separation, the mixture of the amines is subjected to fractionaldistillation. Thereby, in addition to unchanged piperidine, pure N-(p-benzyl phenyl pro yD-piperidinehaving a boiling point of b 201 C. is obtained. The yield amounts to 65% if the theory, based on the reacted amount of 'y-phenylpropyl chloride.

EXAMPLE 2 N- lp-( -chlorobeizzyl)phenylpropjd] -piperidine 46 parts of 'y-phenylpropyl chloride are reacted in the manner described in the above Example 1, in the presence of 0.022 part of FeCl, as catalyst, with 16 parts of 4 -chlorobenzyl chloride. Thereby, the full theoretical amount of HCl is split oif already within 15 minutes. The reaction product is further treated in the manner described in Example 1 and then reacted with piperidine. In the purification of the piperidine derivative formed, the desired amine which boils at a pressure of 3 Torr. at 223 -224 C., is obtained in a yield of 65% of the theory, based (like in all other examples) on the reacted amount of 'y-phenylpropyl chloride.

EXAMPLE 3 N-(p-benzylphenylpropyl) -mrph0lirze In preparing this compound, all steps are carried out in the manner described in Example 1, but the piperidine is replaced by an equal amount of morpholine. The N-(p-benzylphenylpropyl)-morpholine thus prepared has a boiling point of b 201 C. and the yield amounts to 63%.

EXAMPLE 4 N p-(4-ch lorobenzyl -phen y lpropyl -m0rph0line if in the reaction described in the above Example 2, the piperidine is replaced by an equal amount of morpholine, the compound N-[p-(4-chlorobenzyl)-phenylpropyll-morpholine having a boiling temperature of b 218- 220 C. is obtained. The yield amounts to about 70%.

EXAMPLE 5 N- [p- (4-ch lorobenzyl) -phenylethyl] -piperidine 42 parts of p-phenylethyl chloride, 16 parts of 4-chlorobenzyl chloride are reacted in the presence of 0.015 part of FeCl according to the procedure described in the above Example 1. The crude product of this reaction is caused to react, at 125 C., after distilling off the unchanged phenylethyl chloride, with about an equal amount of piperidine. By further treatment according to conventional procedure, pure N-[p-(4-chlorobenzyD- phenylethyll-piperidine having a boiling point or" b 204-"- 205 C. is obtained in good yield.

EXAMPLE 6 N- [p- (4-011lorobenzyl-phenylethyl] -m0rpholine This compound is obtained in good yield by substituting morpholine in the procedure described in Example 5. Boiling point: b 224-225 C.

EXAMPLE 7 N p-( wphenylethyl -phenylethyl -piperidine In order to prepare this compound, 168 parts of fl-phenylethyl chloride and 56 parts of wphenyleth'yl chloride are reacted in the presence of 0.05 part of FeC1 The crude product formed and processed in conventional manner is reacted with an equal amount of piperidine and.

yields N-[p-(a-phenylethyl)-phenylethyl] -piperidine having a boiling point of 0 200-20l C.

EXAMPLE 8 N- [p-(et-phcnylethyt') -phenylethyl] morph0line This compound is formed if in the reaction described in the preceding Example 7 the piperidine is replaced by an equal amount of morpholine. The boiling point of the compound is b.; 2l8-219 C.

EXAMPLE 9 N p-methoxy-m- (5 -chl0rothenyl yphenylisobutyl piperidine 119 parts of 'y-(p-inethoxyphenyl)-isobutyl chloride are reacted with 33 parts of S-chlorothenyl chloride in the presence of 0.015 part of FeCl in the manner described in the above Example 1. The intermediate product thus formed is reacted with an equal amount of piperidine, whereby the compound N-[p-methoxy-m-(S-chloro- 4 thenyD-y-phenylisobutyl]-piperidine having a boiling point of b; 222224 C. is formed with good yield.

EXAMPLE 10 N- p-methoxy-m 5 -chl0r0thenyl -'y-phenylis0butyl morpholine This compound is prepared by substituting in the procedure of the preceding Example 9, an equal amount. of morpholine for the piperidine. The compound has a boiling point of b 231 C.

EXAMPLE 11 N p-(4-methoxybenzyl -phenylpr0pyl -m0rpholine A mixture of 773 parts of y-phenylpropyl chloride, 60 parts of paraformaldehyde and 60 parts of anhydrous zinc chloride is vigorously stirred for about 30 minutes under heating to 75 C. Subsequently, dry HCl is introduced at 50 C. under further stirring into the mixture. The HCl is dissolved quickly and practically completely until saturation. After saturation, the mixture is stirred for an additional hour, the reaction product separated from the aqueous phase is diluted with a small amount of ether, successively washed with water, sodium bicarbonate solution and again with Water, dried over calcium chloride and finally subjected to fractional distillation. In the latter, in addition to unchanged phenylpropyl chloride, which has been used here in great excess, 287 parts of p-chloromethyl-'y-phenylpropyl chloride having a boiling point of b l49-l50 C. are obtained. The yield amounts to about of the theory, based on the reacted amount of 'y-phenylpropyl chloride.

40.6 parts of the chloromethylation product t us ob tained are introduced drop by drop during 20 minutes at C. into a mixture of 65 parts of anisol and 0.022 part of FeCl while dry air is passed through the reaction mass. Within 35 minutes the theoretical amount of HCl is split off, whereupon the reaction product is diluted with a small amount of ether and washed successively with dilute hydrochloric acid, water,v sodium bicarbonate solution and again with water. The product is then dried over calcium chloride and subjected to fractional distillation- Thereby, the p-(4-methoxybenzyl)-phenylpropyl chloride boils at 185 C. under a pressure of 15 Torr. The yield amounts to 75% of the theory. By reacting this chloride with an about equal amount of morpholine at C. and processing the reaction product in the manner described in connection with the isolation of N-(p-benzyl-phenylpropyl)-piperidine in the above Example l, N-[p-(4-methoxyphenyl)-phenylpropyl1-morpholine of 92% purity, having a boiling point of b 239- 240 C. are obtained.

EXAMPLE 12 N-[p-(4-methoxy-3-chlorobenzyl)-phenylpropyl]- morpholine 86 parts of o-chloroanisol are reacted with 40.6 parts of p-(chloromethyl)-'y-phenylpropyl chloride with the addition of 0.012 part of FeCl;,. This dichloride is prepared in the present as well as in all of the subsequentexamples, in the manner described in the preceding Example 11.. In. the reaction of the dichloride with o-chloroanisol, the theoretical amount of the HCl is formed at. 100 C. within 20 minutes. The further treatment, which is carried out in the manner described in the preceding example, yields 78% of p-(4-methoxy-3-chlorobenzyl)- phenylpropyl chloride having a boiling point of b 213' C. By reacting this chloride in conventional manner (as described in Example 11) with morpholine, 90% of the compound N- [p-(4-methoxy-3-chlorobenzyl) -phenylpropyll-morpholine having a boiling point of h 242 C. are obtained.

EXAMPLE 13 148 parts of o-butoxytoluene are reacted at 145 C. with 61 parts of p-(chloromethyl)-'y-phenylpropyl chloride, in the presence of FeCl as catalyst, in the manner described in the above Example 11. An amount of 15 parts of the p-(4-butoxy-3-methylbenzyl)-phenylpropyl chloride (having a boiling point of b 217-219 C.) thus formed, are reacted in the manner described in the above Example 12, with 12 parts of morpholine. Thereby, N- [p- (4-butoxy-3-methylbenzyl) -phenylpropyl] -morpholine is formed in a yield of about 60% based on the amount of reacted phenylpropylchloride. The compound has a boiling point of b 245 -246 C.

EXAMPLE 14 N- [p- (4-phenoxybenzyl) -phenylprpyl] -m0rph0line In the preparation of this product, the diphenyl ether is reacted in a manner similar to that described in connection with anisol in Example 11. This procedure yields pure N- [p- 4-phenoxybenzyl phenylpropyl] -morpho1ine having a boiling point of b 263265 C. The yield amounts in the catalytic reaction to about 80% and in the reaction of the chloride with morpholine to about 90% of the theory.

EXAMPLE 15 N- [p-thenylphenylpropyl] -morph0line EXAMPLE 16 N- [p- (S-chlorothenyl)phenylpropyl] -m0rph0li ne The chlorothiophene is reacted with p-(chloromethyD- phenylpropyl chloride without the use of the nitrobenzene solvent, but otherwise in the manner described in the preceding Example 15. The N- [p-(S-chlorothenyl)-phenylpropylJ-morpholine, which is obtained in good yield, boils at 216-218 C. at 1.6 Torr.

EXAMPLE 17 N p- -chlor0thenyl -phenylpr0pyl -piperidine By replacing in preceding Example 16 the morpholine by piperidine, N- [p-S-chlorothenyl)-phenylpropyl]piperidine having a boiling point of b 198200 C., isobtained in a similar manner and in likewise good yield.

EXAMPLE 18 N p- (4-methoxybenzyl -phenylethyl -m0rph0line Phenylethyl chloride is chloromethylated in a manner analogous to that described in connection With phenylpropyl chloride in the above Example 11.- 38 parts of the resulting p-(chloromethyl)-phenylethyl chloride (boiling point b l45147 C.) are reacted at 100 C. with 65 parts of anisol in the presence of 0.020 part of Fe O or FeCl The reaction, which takes place within a rather short time, yields by proceeding in a manner corresponding to that described in the above Example 11, pure p-(4-methoxybenzyl)-phenylethyl chloride having a boiling point of b 185 186 C. Fifteen parts of this compound are reacted with an equal amount of morpholine. By conventional procedure, 16.5 parts (=92% of the theory) of pure N[p-(4-methoxybenzyl)-phenylethyH-morpholine having a boiling point of b, 218 to 220 C. are obtained. a

'6 EXAMPLE .19

N p-thenyl-phenylethyl] -morphaline By replacing in the above Example 15 the p-(chloromethyl)-phenylpropyl chloride by an equal amount of p-(chloromethyl)-phenylethyl chloride and proceeding otherwise in the manner described in said example, the compound N-[p-thenyl-phenylethyl]-rnorph=oline having a boiling point b l98200 C. is obtained in good yield.

as the end product.

EXAMPLE 2O N-[p-thenyl-phenylethyl]-piperidine This compound is obtained in good yield by replacing in the reactions according to the preceding Example 19, the morpholine by an equal amount of piperidine. It has a boiling point of b 195 -197 C.

EXAMPLE 21 N- [p-(3,4-dimethoxybenzyl) -phenylpropyl] -m0rph0line By replacing in the reactions described in the above Example 12 the o-chloroanisol by an equal amount of veratrole, the pure compound N-[p-(3,4-dimethoxybenzyl)-phenylpropyl]-morpholine having a. boiling point of b 232-234 C. is obtained. The yield amounts to 60% of the theory, based on the amount of reacted 4- (chlorornethyl)-phenylpropyl chloride.

EXAMPLE 22 N p- (2,4,6 -trimethylbenzyl -pheny lpropyl -m0rph0line By replacing in the reactions described in the above Example 12 the o-chloroanisol by an equal amount of mesitylene, the compound N[p-(2,4,6-trimethyl-benzyl)- phenylpropylJ-mor'pholine having a boiling point of h 233235 C. results, in a yield of about 60%.

EXAMPLE 23 N p-theny l-pheny lpropyl -m0rph0line EXAMPLE 24 N [p-(4-phen0xybenzyl) -phenylpr0pyl] -m0rpholine This compound can be preparedin satisfactory manner by the ingredients and the procedure described in the above Example 14, also if the 0.022 part of FeCl is replaced by 0.01 part of AlCl as catalyst in said procedure.

EXAMPLE 25 N- [p-(4-fluorobenzyl) -phenylpropyll -piperidine This compound, which has a boiling point of b 193 -194 C., is obtained with a yield of of the theory, by reacting in conventional manner 14.6 parts of piperidine with 15 parts of p-(4-fluorobenzyl)-phenylpropylchloride, which has a boiling point of b 161 C. This dihalogenide is prepared by reacting 4- fluorobenzyl chloride with 'y-phenylpropyl chloride in a manner similar to that of the treatment of 4-chloro-benzyl chloride, described in the above Example 2. The p-(4-fluorobenzyl)-phenylpropyl chloride can be also obtained by reacting 71 parts of fluorobenzene with 30.5 parts of p- (chloromethyl)-phenylpropyl chloride at 90 C. in the presence of 0.19 part of AlCl as catalyst.

EXAMPLE 26 N-(p-benzylphenylpr0pyl)-piperidine In addition to benzylchloride, as described. in Example aeazneee i 1, the above compound can be prepared also from benzene in the following manner.

90 parts of benzene are reacted with 30.5 parts of p-(chloromethyl)-phenylpropyl chloride in the presence of 0.11 part of AlCl in conventional manner. The resulting p-benzylphenylpropyl chloride is then reacted at 125 C. with an equal amount of piperidine.

In the present application the parts and percent refer to parts and percent by weight, if not otherwise stated. In the statement of boiling points, the pressure, it different from one atmosphere, is indicated by a subscript; for example b 200 means boils at 200 if the pressure is 10 mm. Hg. The term Torr. is a unit of pressure equal to of onenormal atmospheric pressure.

It will be understood that the present invention is not limited to the specific materials, proportions, solvents, conditions and other details specifically described above and can be carried out with variousmodifications without departing from the scope of the invention, as defined in the appended claims. The catalysts are used in about the range of the proportions described above. instead of the compounds of Fe, Zn'and Al specifically described above, other compounds of these metals can also be used. The terms aryl and thienyl radicals are used in the present application to also include substituted aryl and substituted thienyl radicals.

What is claimed is:

1. A new compound corresponding to the general formula on otm-tom)n.x RI

wherein R stands for a radical selected from the group consisting of phenyl, 4-fluorophenyl, 4-chlorophenyl, 4- methoxyphenyl, 4-butoxyphenyl, 4-phenoxyphenyl, 4- methoXy-3-chlorophenyl, 3,4-dimethoxyphenyl, 2,4,6-tri methylphenyl, thienyl and S-chlorothienyl radicals; R is selected from the group consisting of H and CH X is selectedfrom the group consisting of morpholine and piperidine radicals and n is an integer having a value in the range of 2-4.

2. As a new compound N-(p-benzylphenylpropyl)'- morpholine.

3. As a new compound N-[p-(4-chlorobenzyl)-phenylpropyl] -morpholine.

4. As a new compound N-[p-(u-phenylethyl)-phenylethyl] -morpholine.

5. As a new compound N-[p-(4-methoxybenzyl)-phenylpropyl] -morpholine.

v6. As a new compound N-[p-(S-chlorothenyl)phenylpropyl]-morpholine.

7. A process for preparing a compound corresponding to the generalformula CHF-CaHr-(CHBMJI wherein R stands for a radical selected from the group consisting of phenyl, 4-fluorophenyl, 4-chlorophenyl, 4- methoxyphenyl, 4-butoxyphenyl, 4-phenoxyphenyl, 4- methoxy-il-chlorophenyl, 3,4-dimethoxyphcnyl, 2,4,6-trimethylphenyl, 'thienyl and S-chlorothienyl radicals; R is selected from the group consisting of H and CH X is selected from the group consisting of morphoiine and piperidine radicals and n is an integer having a value in the range of 2-4, comprising substituting in a phenylalkyl halogenide of the general formula C H --(CH -'halogen, wherein n has the above defined meaning, an H atom of the phenyl radical by a radical selected from the group consisting of benzyl and thenyl ralicals and subsequently reacting the resulting product with an aminein order to replace the halogen by an amine radical.

8. A process as claimed in claim 7, in which a compound of the formula C H -(CH ),,.Cl is reacted with a compound of the general formula in the presence of a catalyst selected from the group consisting of the compounds of iron, zinc and aluminum, and used in a minimum amount within the range of (Ml-0.187% based on the total weight of the reaction components, and the resulting product is reacted with an amine selected from the group consisting of piperidine and morpholine in order to replace the Cl-atom by the radical of the amine.

9. A process as claimed in claim 7, in which a compound of the formula C H (CH C1 is subjected to chloromethylation to form a compound of the formula Cl.CH -C H (CH ),,.Cl, the resulting product is reacted in the presence of a catalyst selected from the group consisting of compounds of iron, zinc and aluminum, and used in a minimum amount within the range of 0.01-0.0l87% based on the total Weight of the reaction components, with a compound of the formula RH and the reaction product is treated with an amine selected from the group consisting of piperidine and morpholine in order to replace the Cl-atom by the radical of the amine.

No references cited. 

1. A NEW COMPOUND CORRESPONDING TO THE GENERAL FORMULA
 6. AS A NEW COMPOUND N-(P-(5-CHLOROTHENYL)-PHENYLPROPYL)-MORPHOLINE. 